Pharmacological induction of membrane lipid poly-unsaturation sensitizes melanoma to ROS inducers and overcomes acquired resistance to targeted therapy

by Selleckchem | Aug 12 2023

Background: One of the key limitations of targeted cancer therapies is the rapid onset of therapy resistance. Taking BRAF-mutant melanoma as paradigm, we previously identified the lipogenic regulator SREBP-1 as a central mediator of resistance to MAPK-targeted therapy. Reasoning that lipogenesis-mediated alterations in membrane lipid poly-unsaturation lie at the basis of therapy resistance, we targeted fatty acid synthase (FASN) as key player in this pathway to evoke an exquisite vulnerability to clinical inducers of reactive oxygen species (ROS), thereby rationalizing a novel clinically actionable combination therapy to overcome therapy resistance.

Methods: Using gene expression analysis and mass spectrometry-based lipidomics of BRAF-mutant melanoma cell lines, melanoma PDX and clinical data sets, we explored the association of FASN expression with membrane lipid poly-unsaturation and therapy-resistance. Next, we treated therapy-resistant models with a preclinical FASN inhibitor TVB-3664 and a panel of ROS inducers and performed ROS analysis, lipid peroxidation tests and real-time cell proliferation assays. Finally, we explored the combination of MAPK inhibitors, TVB-3664 and arsenic trioxide (ATO, as a clinically used ROS-inducer) in Mel006 BRAF mutant PDX as a gold model of therapy resistance and assessed the effect on tumor growth, survival and systemic toxicity.

Results: We found that FASN expression is consistently increased upon the onset of therapy resistance in clinical melanoma samples, in cell lines and in Mel006 PDX and is associated with decreased lipid poly-unsaturation. Forcing lipid poly-unsaturation in therapy-resistant models by combining MAPK inhibition with FASN inhibition attenuated cell proliferation and rendered cells exquisitely sensitive to a host of ROS inducers. In particular, the triple combination of MAPK inhibition, FASN inhibition, and the clinical ROS-inducing compound ATO dramatically increased survival of Mel006 PDX models from 15 to 72% with no associated signs of toxicity.

Conclusions: We conclude that under MAPK inhibition the direct pharmacological inhibition of FASN evokes an exquisite vulnerability to inducers of ROS by increasing membrane lipid poly-unsaturation. The exploitation of this vulnerability by combining MAPK and/or FASN inhibitors with inducers of ROS greatly delays the onset of therapy resistance and increases survival. Our work identifies a clinically actionable combinatorial treatment for therapy-resistant cancer.

Comments:

The given background describes a study conducted on BRAF-mutant melanoma, which is known for its rapid onset of therapy resistance. The researchers focused on identifying the role of lipogenesis and membrane lipid poly-unsaturation in therapy resistance and explored potential combination therapies to overcome this resistance.

The researchers first analyzed gene expression and lipidomics data from melanoma cell lines, patient-derived xenografts (PDX), and clinical datasets to investigate the association between the expression of fatty acid synthase (FASN), a key regulator of lipogenesis, and membrane lipid poly-unsaturation as well as therapy resistance.

They found that FASN expression was consistently increased in therapy-resistant melanoma samples across different datasets, including clinical samples, cell lines, and PDX models. This increase in FASN expression was accompanied by decreased lipid poly-unsaturation, suggesting a potential link between altered lipogenesis and therapy resistance.

To further explore this association, the researchers treated therapy-resistant models with a preclinical FASN inhibitor called TVB-3664, along with a panel of reactive oxygen species (ROS) inducers. They conducted ROS analysis, lipid peroxidation tests, and real-time cell proliferation assays to evaluate the effects of these treatments.

The results showed that combining MAPK inhibition (targeted therapy) with FASN inhibition resulted in increased membrane lipid poly-unsaturation and significantly attenuated cell proliferation in therapy-resistant models. Importantly, this combination also rendered the cells highly sensitive to a variety of ROS inducers. One specific ROS-inducing compound tested was arsenic trioxide (ATO), which is already used clinically.

To validate the findings in a more clinically relevant setting, the researchers utilized a BRAF mutant PDX model called Mel006, which is known for its therapy resistance. They investigated the effect of combining MAPK inhibitors, FASN inhibitor (TVB-3664), and ATO on tumor growth, survival, and systemic toxicity in this model.

The results demonstrated that the triple combination therapy significantly increased the survival of the Mel006 PDX models from 15% to 72% without causing noticeable signs of toxicity. This finding suggests that the combination of MAPK inhibition, FASN inhibition, and ATO as a clinically used ROS-inducer could be an effective strategy to overcome therapy resistance in BRAF-mutant melanoma.

In conclusion, the study highlights the role of FASN in therapy resistance and the importance of membrane lipid poly-unsaturation in melanoma. The combination of MAPK inhibitors and FASN inhibitors increases lipid poly-unsaturation and sensitizes therapy-resistant cells to ROS inducers, resulting in improved survival. This research provides a promising and clinically actionable combinatorial treatment approach for therapy-resistant cancer, specifically BRAF-mutant melanoma.